Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children Now Online

demonstrate this. Antibody titers decline during effective therapy. A Coccidiodes EIA has been developed that detects and quantifies coccidioidal galactomannan concentrations in urine samples 34,43,44 and is especially useful in serious infections and/or instances in which antibody is undetectable. Dissociation of immune complexes has increased the sensitivity of detection of coccidioidal antigen in serum. 44 Meningitis has been diagnosed using real-time PCR analysis of CSF. 36

Most illnesses are primary infections with rates governed by both environmental conditions that are conducive to fungal growth and to activities/conditions that predispose to inhalation of spores. Increased infection rates have been attributed to population shifts to endemic regions, climatic conditions, and better recognition. 10

Panel's Recommendations
• Routine use of antifungal medications for primary prophylaxis of coccidioidal infections in children is not recommended (BIII).
• Diffuse pulmonary or disseminated infection (not involving the central nervous system) should be treated initially with amphotericin B (AII*). After completion of amphotericin B, treatment with fluconazole or itraconazole should begin (BIII). Alternatively, some experts initiate therapy with amphotericin B combined with a triazole, such as fluconazole, in patients with disseminated disease and continue the triazole after amphotericin B is stopped (BIII).
• There is no evidence that lipid preparations of amphotericin are more effective than amphotericin B deoxycholate for the treatment of coccidioidomycosis. Lipid preparations are often preferred because they are better tolerated and associated with less nephrotoxicity than amphotericin B deoxycholate (AII*).
• Itraconazole is preferred for treatment of skeletal infections (AII*).
• Because absorption of itraconazole varies from patient to patient, serum concentrations should be measured to ensure effective, non-toxic levels of drug, monitor drug levels following changes in dosage, and assess compliance (BIII).
• Amphotericin B preparations are not the drugs of choice for treating coccidioidal meningitis; fluconazole is the preferred drug for treating coccidioidal meningitis (AII*).
Impairment of cellular immunity is a major risk factor for severe primary coccidioidomycosis or relapse of past infection. In HIV-infected adults, both localized pneumonia and disseminated infection usually are  observed in individuals with CD4 T lymphocyte (CD4) cell counts <250 cells/mm 3 . 14,15 The threshold for  increased risk in HIV-infected children has not been established; systemic fungal infection has occurred  when CD4 counts were ≤100 cells/mm 3 and with CD4 percentages <15%, both indicative of severe immunosuppression. 16,17 Although no cases of coccidioidomycosis were reported in HIV-infected children enrolled in the Perinatal AIDS Collaborative Transmission Study, the study sites under-represented geographic regions in which coccidioidomycosis is endemic. 18 Women who acquire coccidioidomycosis late in pregnancy are at risk of dissemination, but infection in their infants is infrequent. 19 Infections in infants usually result from inhalation of spores in the environment. In adults, combination antiretroviral therapy (cART) appears to be responsible for the declining incidence and severity of coccidioidomycosis. 20,21 Data are limited in children.

Clinical Manifestations
Coccidioidal infection can range from a mild, self-limited, flu-like illness to more severe, focal or disseminated illness, including pneumonia, bone and joint infection and meningitis. Immunocompromised individuals and previously healthy blacks, Hispanics, and Filipinos with coccidioidomycosis are at increased risk of dissemination, as are pregnant women who acquire coccidioidal infection during the second or third trimester 22 or the postpartum period. 23,24 The severity of clinical manifestations in HIV-infected adults varies in direct proportion to the degree of immunocompromise. Diffuse pulmonary infection and extrathoracic dissemination have been associated with decreased CD4 counts, increased HIV RNA levels, and lower likelihood of having received potent antiretroviral therapy (ART). 21 Focal pneumonitis can occur in mild to moderately immunocompromised patients. 15,24 Pleural inflammation may result in effusion, empyema, and/or pneumothorax. 25 If untreated, a coccidioidal antibody-seropositive, HIV-infected individual is at risk of serious disease, with the degree of severity inversely proportional to absolute CD4 counts <250/mm 3 . Bone and joint involvement is rare in HIV-infected patients. 20,26 Children with primary pulmonary infection may present with fever, malaise, and chest pain. The presence of cough varies, and hemoptysis is rare. Persistent fever may be a symptom of extrathoracic dissemination. Children with meningitis may present with headaches, altered sensorium, vomiting, and/or focal neurologic deficits. [27][28][29] Fever is sometimes absent, and meningismus occurs in only 50% of patients. Hydrocephalus complicating basilar inflammation 27,30 occurs in most (83%-100%) children with coccidioidal meningitis. 27,31 Generalized lymphadenopathy, skin nodules, plaques or ulcers, 24,32 peritonitis, and liver abnormalities also may accompany disseminated disease.

Diagnosis
Because signs and symptoms are non-specific, the diagnosis of coccidioidomycosis should be among those considered in patients who reside in or have visited endemic areas. 25,33 Culture, microscopy, and serology have been the methods used for diagnosis, but newer tests, including coccidioidal galactomannan antigen detection in urine, 1,34 are especially useful for diagnosis in immunocompromised hosts. Polymerase chain reaction (PCR) assays that target specific coccidioidal genes have been developed but are not yet commercially available. 35,36 In patients with meningitis, cerebrospinal fluid (CSF) shows moderate hypoglycorrhachia, elevated protein concentration, and pleocytosis with a predominance of mononuclear cells. CSF eosinophilia may also be present. The observation of distinctive spherules containing endospores in histopathologic tissue 37 or other clinical specimens is diagnostic. Stains of CSF in patients with meningitis usually are negative. Pyogranulomatous inflammation with endosporulating spherules is seen in affected tissue specimens with haematoxylin and eosin. Spherules can also be observed using Papanicolaou, Gomori methenamine silver nitrate, and periodic acid-Schiff stains. Cytologic stains are less reliable for diagnosing pulmonary coccidioidomycosis, and a negative cytologic stain on a clinical respiratory specimen may not exclude active pulmonary coccidioidomycosis. 26 Potassium hydroxide stains are less sensitive and should not be used. 26 Growth of Coccidioides spp. is supported by many conventional laboratory media used for fungal isolation; growth may occur within 5 days at 30°C to 37°C. 26 Blood cultures are positive in <15% of cases; CSF cultures are positive in <50% of children with meningitis. 24,26,38 Cultures of respiratory specimens are often positive in adults with pulmonary coccidioidomycosis. The laboratory should be alerted to clinical suspicion of coccidioidal infection so that specimens can be handled in secure and contained fashion to minimize hazards to laboratory personnel.
Serologic assays, performed by enzyme-linked immunoassay (EIA), immunodiffusion, or classical tube precipitin or complement fixation methodology that measure coccidioidal Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibody are valuable aids in diagnosis 39 but may be falsely negative in immunocompromised hosts. Presence of IgM-specific coccidioidal antibody suggests active or recent infection although, in instances in which IgG-specific antibody is absent, data are conflicting about potential false positives. 40,41 IgG-specific antibody appears later and persists for 6 to 8 months. A commercial EIA appears more sensitive than the older tube precipitin and complement fixation tests and the immunodiffusion assays, although concern remains about specificity. 42 The EIA, however, is not quantitative. 24 Assays for coccidioidal antibody in serum or body fluids such as CSF provide diagnostic and prognostic information.
Cross-reactivity can occur with other endemic mycoses. IgG-specific antibody titers often become undetectable in several months if the infection resolves. The diagnosis of meningitis is established with either a positive CSF culture or detection of IgG-specific antibody in CSF. Serial testing 36 following at least a 2week interval may be needed to demonstrate this. Antibody titers decline during effective therapy. A Coccidiodes EIA has been developed that detects and quantifies coccidioidal galactomannan concentrations in urine samples 34,43,44 and is especially useful in serious infections and/or instances in which antibody is undetectable. Dissociation of immune complexes has increased the sensitivity of detection of coccidioidal antigen in serum. 44 Meningitis has been diagnosed using real-time PCR analysis of CSF. 36

Preventing Exposure
HIV-infected patients who reside in or visit regions in which coccidioidomycosis is endemic cannot completely avoid exposure to Coccidioides spp., but risk can be reduced by avoiding activities and/or exposure to sites that may predispose to inhalation of spores. These include disturbing contaminated soil, archaeological excavation, and being outdoors during dust storms. If such activities are unavoidable, use of high-efficiency respiratory filtration devices should be considered. 36

Preventing First Episode of Disease
No prospective studies have been published that examine the role of prophylaxis to prevent development of active coccidioidomycosis in patients without previous (recognized) episodes of coccidioidomycosis. Although some experts would provide prophylaxis with an azole (fluconazole) to coccidioidal antibodypositive HIV-infected patients living in regions with endemic coccidioidomycosis, others would not. 26 Chemoprophylaxis is used for coccidioidal antibody-positive HIV-infected adults living in endemic areas and with CD4 counts <250 cells/mm 3 . 45,46 However, given the low incidence of coccidioidomycosis in HIVinfected children, the potential for drug interactions, potential for development of antifungal drug resistance, and the cost, the routine use of antifungal medications for primary prophylaxis of coccidioidal infections in children is not recommended (BIII).

Discontinuing Primary Prophylaxis
Not applicable.

Treating Disease
In patients with HIV infection, effective cART, if not being administered at the time of diagnosis of coccidioidomycosis, should be started in concert with initiation of antifungal agents. Treatment protocols that are recommended for HIV-infected children are based on experience in nonrandomized, open-label studies in adults. Physicians who infrequently treat children with coccidioidomycosis should consider consulting with experts.
Antifungal therapy had been a recommendation for all HIV-infected adults with clinically active, mild coccidioidomycosis. 47 More recently, treatment protocols appropriate for patients who are HIV-uninfected have been suggested 47 for HIV-infected adults reliably receiving potent ART and who have CD4 counts >250 cells/ mm 3 . 46 That would include patients with mild infections that are not accompanied by signs suggestive of dissemination, diffuse pulmonary infiltrates, or meningitis. In this setting, patients should be closely monitored to ensure compliance with ART, effective HIV suppression, and maintenance of CD4 counts >250 cells/mm 3 . Management should also include education directed at reducing the probability of re-exposure to coccidioidal spores. In children, absent comparable published experience in this setting, expert consultation should be sought and, if treatment is elected, recommendations should be based upon assurance of continued compliance with ART, confirmation of continued HIV suppression, CD4 counts >250/mm 3 , education directed at decreasing the likelihood of exposure to coccidioidal spores, and close medical follow up.
For patients with mild, non-meningitic disease (e.g., focal pneumonitis), monotherapy with fluconazole or itraconazole is appropriate given their effectiveness, safety, convenient oral dosing, and pharmacodynamic parameters (BII*). Fluconazole (6-12 mg/kg/day) and itraconazole (5-10 mg/kg/dose twice daily for the first 3 days, followed thereafter by 2-5 mg/kg per dose twice daily) are alternatives to amphotericin B for children who have mild, non-meningitic disease (BIII). In a randomized, double-blind trial in adults, fluconazole and itraconazole were equivalent for treating non-meningeal coccidioidomycosis. Itraconazole (5 mg/kg body weight dose twice daily) appeared to be more effective than fluconazole for treating skeletal infections (AII*). 48 Severely ill patients with diffuse pneumonia and/or other signs of probable disseminated infection (not involving the CNS) are initially treated with an amphotericin B preparation because these appear to evoke a faster therapeutic response than do the azoles. 49,50 Although there is no evidence that the lipid preparations are more effective than amphotericin B deoxycholate, lipid formulations often are used because they are better tolerated (AIII). The length of amphotericin B therapy is governed by both the severity of initial symptoms and the pace of the clinical improvement. Thereafter, amphotericin B is stopped and treatment with fluconazole or itraconazole begun (BIII). Some experts initiate therapy with both amphotericin B and a triazole, such as fluconazole, in patients with severe disseminated disease and continue the triazole after amphotericin B is stopped (BIII). 26,48 The total duration of therapy should be ≥1 year. 26 Meningitis is a life-threatening manifestation of coccidioidomycosis and consultation with experts should be considered (BIII). Successful treatment requires an antifungal agent that achieves effective concentrations in CSF. Intravenous amphotericin B achieves poor CSF concentrations and is therefore not recommended for treating coccidioidal meningitis (AIII). The relative safety and comparatively superior ability of fluconazole to penetrate the blood-brain barrier have made it the treatment of choice for coccidioidal meningitis (AII*). An effective dose of fluconazole in adults is 400 mg/day, but some experts begin therapy with 800 to 1000 mg/day. 47 Children usually receive 12 mg/kg/dose once daily (800 mg/day maximum) (AII*). 51,52 The 12 mg/kg dosage may be required to attain serum concentrations equivalent to those in adults receiving 400 mg/day. 53 Some experts would begin at a dose of 15 to 23 mg/kg/day. 24 Successful therapy with posaconazole 54 and voriconazole has been described in adults but there is no published experience in children. 55 Some experts use amphotericin B administered intrathecally 50,56 in addition to an azole. Intrathecal amphotericin administration adds additional toxicity and is not used as part of initial therapy (CIII). Despite the benefits afforded by the azoles for treating meningitis, a retrospective analysis of outcomes in adults treated for coccidioidal meningitis in the pre-azole (earlier than 1980) compared with outcomes in the azole era found that a similar percentage developed serious complications, including stroke and hydrocephalus; risk factors for acquiring coccidioidal meningitis in the azole era included immunocompromised state, with one-third of patients in this group having HIV/AIDS. 28

Monitoring and Adverse Events (Including IRIS)
In addition to monitoring patients for clinical improvement, some experts 26 have recommended monitoring coccidioidal IgG antibody titers to assess response to therapy. Titers should be obtained every 12 weeks (AIII).
If therapy is succeeding, titers should decrease progressively; a rise in titers suggests recurrence of clinical disease. However, if serologic tests initially were negative, titers during effective therapy may increase briefly and then decrease. 26 This lag in response during the first 2 months of therapy should not necessarily be construed as treatment failure.
Adverse effects of amphotericin B are primarily those associated with nephrotoxicity. Infusion-related fevers, chills, nausea, and vomiting also can occur, although they are less frequent in children than in adults. Lipid formulations of amphotericin B have lower rates of nephrotoxicity. Hepatic toxicity, thrombophlebitis, anemia, and rarely neurotoxicity (manifested as confusion or delirium, hearing loss, blurred vision, or seizures) also can occur (see discussion on monitoring and adverse events in Candida infection). Intrathecal injection of amphotericin B may result in arachnoiditis. 57,58 Triazoles can interact with other drugs metabolized by CYP450-dependent hepatic enzymes, 59,60 and the potential for drug interactions should be assessed before initiation of therapy (AIII). Use of fluconazole or itraconazole appears to be safe in combination with ART. Voriconazole should be avoided in patients receiving protease inhibitors (BIII) 61 or non-nucleoside reverse transcriptase inhibitors. 15 The most frequent adverse effects of fluconazole are nausea and vomiting. Skin rash and pruritus may be observed, and cases of Stevens-Johnson syndrome have been reported. Asymptomatic increases in transaminases occur in 1% to 13% of patients receiving azole drugs. In HIV-infected patients, fluconazole at high doses can cause adrenal insufficiency. 62 Because absorption of itraconazole varies from patient to patient, serum concentrations should be measured to ensure effective, non-toxic levels of drug, monitor changes in dosage, and assess compliance (BIII).
Coccidioidomycosis-associated immune reconstitution inflammatory syndrome following the initiation of ART has not been reported in children and is rarely reported in adults. 63

Managing Treatment Failure
The treatment of coccidioidomycosis unresponsive to standard therapy has been reviewed; the majority of experience has been in adults. 55 Posaconazole was effective in 6 adults with disease refractory to treatment with other azoles and to amphotericin B 64 and has been used successfully in 73% of 15 adults whose infections were refractory to previous therapy. 65 Posaconazole has also been effective for chronic refractory meningitis unresponsive to fluconazole. 54 Voriconazole was effective in treating coccidioidal meningitis and non-meningeal disseminated disease in adults who did not respond to fluconazole or were intolerant of amphotericin B. 66,67,68 Monotherapy with caspofungin successfully treated disseminated coccidioidomycosis in a renal transplant patient intolerant of fluconazole and other adults in whom conventional therapy failed. 69,70 Others have used caspofungin in combination with fluconazole. 71 Adjunctive interferon-gamma (IFN-γ) 72 was successfully used in a critically ill adult with respiratory failure who did not respond to amphotericin B preparations and fluconazole. 73 However, no controlled clinical studies or data exist for children; thus, adjunctive IFN-γ is not recommended for use in HIV-infected children (BIII).
In instances in which patients with coccidioidal meningitis fail to respond to treatment with azoles, both systemic amphotericin B and direct instillation of amphotericin B into the intrathecal, ventricular, or intracisternal spaces, with or without concomitant azole treatment, have been used successfully. These regimens are recommended in such instances (AIII). 48,52 The basilar inflammation that characteristically accompanies coccidioidal meningitis often results in obstructive hydrocephalus requiring placement of a CSF shunt. Thus, development of hydrocephalus in coccidioidal meningitis does not necessarily indicate treatment failure. Response rates with the azoles can be excellent, but cures are infrequent. Relapse after cessation of therapy is common, occurring in as many as 80% of patients. 74 Thus, indefinite continuation of fluconazole therapy is recommended for patients who have coccidioidal meningitis (AII*).

Preventing Recurrence
Lifelong suppression (secondary prophylaxis) is recommended for patients following successful treatment of meningitis. Relapse after successful treatment of disseminated coccidioidomycosis can occur and lifelong antifungal suppression with either fluconazole or itraconazole should be used (AII*). Secondary prophylaxis should be considered for children with mild disease and ongoing CD4 counts <250 cells/mm 3 or CD4 percentages <15% (BIII). 26,47,49,75,76

Discontinuing Secondary Prophylaxis
In disseminated infection, continued suppressive therapy (secondary prophylaxis) with fluconazole or itraconazole is recommended after completion of initial therapy. Patients with diffuse pulmonary disease, disseminated disease, or meningeal infection should remain on lifelong prophylaxis-even if immune reconstitution is achieved with ART 26 -because of high risk of relapse (AII*). In HIV-infected adults with focal coccidioidal pneumonia who have clinically responded to antifungal therapy and have sustained CD4 counts >250 cells/mm 3 on ART, some experts would discontinue secondary prophylaxis after 12 months of antifungal therapy with careful monitoring for recurrence with chest radiographs and coccidioidal serology. However, only a small number of patients have been evaluated, and the safety of discontinuing secondary prophylaxis after immune reconstitution with ART in children has not been studied. Therefore, in HIVinfected children, once secondary prophylaxis is initiated for an acute episode of milder, non-meningeal coccidioidomycosis, lifelong suppressive therapy should be considered, regardless of ART and immune reconstitution (BIII).

Primary Prophylaxis
N/A N/A Primary prophylaxis not routinely indicated in children.

Secondary Prophylaxis
Fluconazole 6 mg/kg body weight (maximum 400 mg) by mouth once daily Options should be discussed with an expert in the treatment of coccidioidomycosis.
Chronic suppressive therapy (secondary prophylaxis) with fluconazole or itraconazole is routinely recommended following initial induction therapy for disseminated disease and is continued lifelong for meningeal disease.

Therapy with amphotericin results
In a more rapid clinical response in severe, non-meningeal disease.
Meningeal Infection: • Fluconazole 12 mg/kg body weight (maximum 800 mg) IV or by mouth once daily followed by secondary lifelong prophylaxis.